CELL SIGNALING AND METABOLISM (CSM) PROGRAM PROJECT SUMMARY The renamed Cell Signaling and Metabolism (CSM) Program incorporates three central Themes; New Target Discovery Theme, Cancer Metabolism Theme, and the Cell Signaling and the Microenvironment Theme. The scientific goals of the Program are to better understand cancer biology through use of multi-omics platforms in order to identify and assess new targets of opportunity and therapeutic approaches. The Program has considerable strength in new discovery through integration of genomic and epigenomic deconvolution approaches, coupled together with metabolomics to inform on putative signaling pathways. The Program has 40 Research members, 23 Clinical, 7 Adjunct and 3 Shared members who interact via thematic subgroup meetings and the Disease Working Groups. Members represent 16 basic science and clinical departments, including Molecular and Human Genetics, Biochemistry and Molecular Biology, Molecular and Cellular Biology, Pathology and Immunology, Molecular Physiology and Biophysics, Medicine, Pediatrics, Surgery, and Obstetrics and Gynecology. Members focus on multiple different cancer types including pancreas, gastrointestinal, liver, lung, prostate, bladder, and head and neck cancers. During the last budget year, the CSM Program had a total direct funding of $14.2 million that included $4.2 million in NCI funding, $2 million from other NIH institutes, $4.7 million direct in other peer-reviewed funding, and $3.4 million direct from other non-peer reviewed funding. During the previous 5 years, Program members have published a total of 706 manuscripts with 24% resulting from intra- programmatic collaborations, 18% inter-programmatic, and 73% from inter-institutional collaborations. Several publications and joint funding have resulted from an enhanced communication effort between members via thematic subgroup interactions. In particular, considerable effort has been made and future plans include use of multi-omic approaches to identify targetable altered signaling pathways that are informed by metabolic interrogation. This includes a focus to identify pan-cancer alterations. These efforts are also based on catchment area issues, including smoking and obesity, in particular. In addition, considerable effort is focused on identifying biological mechanisms that underlie health care disparity. Future directions include expanding formal career enhancement and trainee educational efforts via enhanced communication and programs. Specific Aims are: 1. To identify and characterize the overlapping molecular underpinnings and pathways regulating metabolic rewiring to delineate key common molecular mediators associated with cancer onset and progression. 2. To evaluate actionable signaling pathways and biological targets that are causal or a consequence of metabolic and molecular mediators of cancer progression. 3. To enact translation of key findings through interactions with the Center for Drug Discovery, the Therapeutic Innovation Center, and the Disease Working Groups to foster development of novel diagnostic, prognostic, and therapeutic approaches.